Addition of phenylisocyanate to 3,5-diphenyl-1,2-dithiolium-4-olate gives a thioketone

The Type B mesoionic heterocycle, 3,5-diphenyl-1,2-dithiolium-4-olate, reacts with phenylisocyanate producing a thioketone derivative rather than a pseudo-semi-conjugated heterocyclic mesomeric betaine. The structure of the thioketone product was confirmed by an X-ray crystallographic investigation

Identification and Characterisation of an Iron-Responsive Candidate Probiotic

Background: Iron is an essential cofactor in almost all biological systems. The lactic acid bacteria (LAB), frequently employed as probiotics, are unusual in having little or no requirement for iron. Iron in the human body is sequestered by transferrins and lactoferrin, limiting bacterial growth. An increase in the availability of iron in the intestine by bleeding, surgery, or under stress leads to an increase in the growth and virulence of many pathogens. Under these high iron conditions, LAB are rapidly out-competed; for the levels of probiotic bacteria to be maintained under high iron conditions they must be able to respond by increasing growth rate to compete with the normal flora. Despite this, iron-responsive genera are poorly characterised as probiotics. Methodology/Principal Findings: Here, we show that a panel of probiotics are not able to respond to increased iron availability, and identify an isolate of Streptococcus thermophilus that can increase growth rate in response to increased iron availability. The isolate of S. thermophilus selected was able to reduce epithelial cell death as well as NF-kB signalling and IL-8 production triggered by pathogens. It was capable of crossing an epithelial cell barrier in conjunction with E. coli and downregulating Th1 and Th17 responses in primary human intestinal leukocytes. Conclusions/Significance: We propose that an inability to compete with potential pathogens under conditions of high iron availability such as stress and trauma may contribute to the lack of efficacy of many LAB-based probiotics in treatin

Recent advances in measuring the effects of diet on gastrointestinal physiology: Sniffing luminal gases and fecal volatile organic compounds.

Despite the huge pool of ideas on how diet can be manipulated to ameliorate or prevent illnesses, our understanding of how specific changes in diet influence the gastrointestinal tract is limited. This review aims to describe two innovative investigative techniques that are helping lift the veil of mystery about the workings of the gut. First, the gas-sensing capsule is a telemetric swallowable device that provides unique information on gastric physiology, small intestinal microbial activity, and fermentative patterns in the colon. Its ability to accurately measure regional and whole-gut transit times in ambulant humans has been confirmed. Luminal concentrations of hydrogen and carbon dioxide are measured by sampling through the gastrointestinal tract, and such application has enabled mapping of the relative amounts of fermentation of carbohydrates in proximal-versus-distal colon after manipulation of the types and amounts of dietary fiber. Second, changes in the smell of feces, via analysis of volatile organic compounds, occur in response to the diet, and by the presence and therapy of irritable bowel syndrome and inflammatory bowel disease. Such information is likely to aid our understanding of what dietary change can do to the colonic luminal microenvironment, and may value-add to diagnosis and therapeutic design. In conclusion, such methodologies enable a more complete physiological profile of the gastrointestinal tract to be created. Systematic description in various cohorts and effects of dietary interventions, particularly when co-ordinated with the analysis of microbiome, are needed

1H NMR-Linked Metabolomics Analysis of Liver from a Mouse Model of NP-C1 Disease

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link

Upper gastrointestinal diseases in patients for endoscopy in South-Western Uganda

Background: There is a paucity of published data regarding upper gastrointestinal diseases in Ugandans with upper gastrointestinal symptoms referred for endoscopy. Objectives: To study the presenting complaints, pathology and Helicobacter pylori prevalence among patients with upper gastrointestinal symptoms in South-Western Uganda. Methods: Patients presenting with upper gastrointestinal symptoms underwent upper endoscopy and a urease test for Helicobacter Pylori, all suspicious lesions were biopsied for histopathology review as appropriate. Results: The most common presenting complaints were epigastric pain (51.6%), dysphagia (13.6%) and odynophagia (7.1%). The most common endoscopy finding was gastritis (40.2%), followed by normal examination (15.2%), oesophageal cancer (13.6%), gastric ulcer (7.6%) and gastric cancer (7.1%). Patients older than 40 years (n=110) had significant findings including gastritis (50.9%), oesophageal cancer (22.7%) and gastric cancer (11.8%). However in younger patients, with the age range of 18-40 years (n=74), most examinations were normal (92.9%). Of the 176 patients able to undergo Helicobacter pylori testing 75.6% were positive. Helicobacter pylori infection was associated with statistically significant increase in gastritis, oesophageal cancer, gastric ulcer, gastric cancer, and duodenal ulcers (p-values< 0.05). Conclusion: Gastritis, ulcerative disease, and upper gastrointestinal malignancies are common in South-Western Ugandans and are associated with a high prevalence of Helicobacter pylori

Nanoscale Si fishbone structures for manipulating heat transport using phononic resonators for thermoelectric applications

Thermoelectric materials have the potential to convert waste heat into electricity, but their thermoelectric efficiency must be improved before they are effective and economically viable. One promising route to improving thermoelectric efficiency in thin-film thermoelectric materials is to reduce the material’s thermal conductivity through nanopatterning the surface. In this work nanoscale phononic resonators are introduced to the surface, and their potential to reduce thermal conductivity is explored via coupled experimental and theoretical techniques. Atomistic modelling is used to predict the dependence of the thermal conductivity on different design parameters and used to guide the design and fabrication of silicon fishbone nanostructures. The nanostructure design incorporates a variation on design parameters such as barb length, width and spacing along the shaft length to enable correlation with changes in thermal conductivity. The thermal characteristics of the nanostructures are investigated experimentally using the spatial resolution of scanning thermal microscopy to correlate changes in thermal conductivity with the changes in the structure parameters. The method developed uses a microheater to establish a temperature gradient along the structure which will be affected by any local variations in thermal conductivity. The impact on the thermal gradient and consequently on the tip temperature is modelled using finite element computer simulations. Experimental changes as small as 7.5% are shown to be detectable in this way. Despite the experimental technique being shown to be able to detect thermal changes far smaller than those predicted by the modelling, no modifications of the thermal conductivity are detected. It is concluded that in order to realise the effects of phononic resonators to reduce thermal conductivity, that much smaller structures with a greater ratio of resonator to shaft will be needed

The role of iron in the pathogenesis of endometriosis: a systematic review

Abstract STUDY QUESTION What is the role of iron in the pathophysiology of endometriosis? SUMMARY ANSWER Iron excess is demonstrated wherever endometriotic tissues are found and is associated with oxidative stress, an inflammatory microenvironment and cell damage; the iron-mediated oxidative stress is independently linked to subfertility, symptom severity and malignant transformation. WHAT IS KNOWN ALREADY Iron is found in excess in endometriotic tissues, and multiple mechanisms have been studied and posited to explain this. It is clear that iron excess plays a vital role in promoting oxidative stress and cell damage. The evidence base is large, but no comprehensive reviews exist to summarise our understanding and highlight the overarching themes to further our understanding and suggest future directions of study for the field. STUDY DESIGN, SIZE, DURATION This systematic review with a thematic analysis retrieved studies from the PubMed, Embase, Web of Science and Cochrane Library databases and searches were conducted from inception through to August 2022. Human and animal studies published in the English language were included and identified using a combination of exploded MeSH terms (‘Iron’ and ‘Endometriosis’) and free-text search terms (‘Iron’, ‘Ferric’, ‘Ferrous’, ‘Endometriosis’, ‘Endometrioma’). PARTICIPANTS/MATERIALS, SETTING, METHODS This review was reported in accordance with the PRISMA guidelines. All studies reporting original data concerning the role of iron or iron complexes in the pathophysiology of endometriosis were included. Studies which did not report original data or provided a review of the field were excluded. Bias analysis was completed for each included study by using the Newcastle-Ottawa scoring system. MAIN RESULTS AND THE ROLE OF CHANCE There were 776 records identified and these were screened down to 53 studies which met the eligibility criteria, including 6 animal and 47 human studies, with 3,556 individual participants. Iron excess is demonstrated in various tissues and fluids, including ovarian endometriomas, ovarian follicles, ectopic endometriotic lesions and peritoneal fluid. Markers of oxidative stress are strongly associated with high iron levels, and aberrant expression of iron-transport proteins has been demonstrated. Abnormal resistance to ferroptosis is likely. Iron-mediated oxidative stress is responsible for a pro-inflammatory micro-environment and is linked to subfertility, symptom severity and, possibly, malignant transformation. LIMITATIONS, REASONS FOR CAUTION A minority of the included studies were of objectively low quality with a high-risk of bias and may lead to misleading conclusions. Additionally, multiple studies failed to appropriately characterise the included patients by known confounding variables such as menstrual cycle phase, which may introduce bias to the findings. WIDER IMPLICATIONS OF THE FINDINGS Current literature depicts a central role of aberrant iron mechanics and subsequent oxidative stress in endometriosis. It is likely that iron excess is at least partly responsible for the persistence and proliferation of ectopic endometriotic lesions. As such, iron mechanics represent an attractive target for novel therapeutics, including iron chelators or effectors of the iron-oxidative stress pathway. There are significant gaps in our current understanding, and this review highlights and recommends several topics for further research. These include the role of iron chelation, resistance to ferroptosis, the relationship between iron excess and localised hypoxia, systemic iron pathophysiology in endometriosis, and the role of oxidative stress in malignant transformation. STUDY FUNDING/COMPETING INTEREST(S) J.W and S.P are supported by clinical fellowships at Liverpool University Hospital NHS Foundation trust. No additional funding was requested or required for the completion of this work. C.J.H. is supported by a Wellbeing of Women project grant (RG2137). D.K.H. is supported by a Wellbeing of Women project grant (RG2137) and MRC clinical research training fellowship (MR/V007238/1). The authors have no conflicts of interest to declare. REGISTRATION NUMBER A protocol was prospectively registered with the PROSPERO database in August 2021 (CRD42021272818) </jats:sec

Lactoferrin impact on gut microbiota in preterm infants with late-onset sepsis or necrotising enterocolitis: the MAGPIE mechanisms of action study

Background: Preterm infants have high rates of morbidity, especially from late-onset sepsis and necrotising enterocolitis. Lactoferrin is an anti-infective milk protein that may act through effects on gut bacteria, metabolites and epithelial cell function. The impact of supplemental lactoferrin in reducing late-onset sepsis was explored in the Enteral LactoFerrin In Neonates (ELFIN) trial. Objectives: The Mechanisms Affecting the Gut of Preterm Infants in Enteral feeding (MAGPIE) study was nested within the ELFIN trial and aimed to determine the impact of lactoferrin on gut microbiota and bacterial function, and changes preceding disease onset. We aimed to explore impacts on the stool bacteria and faecal/urinary metabolome using gas and liquid chromatography–mass spectrometry, and explore immunohistological pathways in resected tissue. Methods: Preterm infants from 12 NHS hospitals were enrolled in the study, and daily stool and urine samples were collected. Local sample collection data were combined with ELFIN trial data from the National Perinatal Epidemiology Unit, Oxford. The longitudinal impact of lactoferrin in healthy infants was determined, and samples that were collected before disease onset were matched with samples from healthy control infants. Established, quality-controlled 16S ribonucleic acid, gas chromatography–mass spectrometry and liquid chromatography–mass spectrometry analyses were conducted. Validated databases and standardised workflows were used to identify bacteria and metabolites. Tissue samples from infants undergoing surgery and matched controls were analysed. Results: We recruited 479 preterm infants (mean gestation of 28.4 ± 2.3 weeks) and collected > 33,000 usable samples from 467 infants. 16S ribonucleic acid bacterial analysis was conducted on samples from 201 infants, of whom 20 had necrotising enterocolitis and 51 had late-onset sepsis, along with samples from healthy matched controls to explore longitudinal changes. The greatest change in relative bacterial abundance over time was observed in Staphylococcus, which decreased from 42 at aged 7–9 days to only 2 at aged 30–60 days (p < 0.001). Small but significant differences in community composition were observed between samples in each ELFIN trial group (R2 = 0.005; p = 0.04). Staphylococcus (p < 0.01), Haemophilus (p < 0.01) and Lactobacillus (p = 0.01) showed greater mean relative abundance in the placebo group than in the lactoferrin group. Gas chromatography–mass spectrometry and liquid chromatography–mass spectrometry analyses showed that lactoferrin had limited impact on the metabolome. Liquid chromatography–mass spectrometry showed significant metabolite differences between necrotising enterocolitis or late-onset sepsis infants and healthy controls. The resected gut tissue analysis revealed 82 differentially expressed genes between healthy and necrotic tissue. Limitations: Although we recruited a large number of infants, collecting daily samples from every infant is challenging, especially in the few days immediately preceding disease onset. Conclusion: We conducted a large mechanistic study across multiple hospital sites and showed that, although lactoferrin significantly decreased the level of Staphylococcus and other key pathogens, the impact was smaller than those of other clinical variables. Immunohistochemistry identified multiple inflammatory pathways leading to necrotising enterocolitis and showed that the use of NHS pathology archive tissue is feasible in the context of a randomised controlled trial. Future work: We observed significant changes in the stool and urinary metabolome in cases preceding late-onset sepsis or necrotising enterocolitis, which provide metabolic targets for a future mechanistic and biomarker study. Trial registration: Current Controlled Trials ISRCTN12554594. Funding: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 14. See the NIHR Journals Library website for further project information

Oral Ferric Maltol Does Not Adversely Affect the Intestinal Microbiome of Patients or Mice, but Ferrous Sulphate Does

From MDPI via Jisc Publications RouterHistory: accepted 2021-06-28, pub-electronic 2021-06-30Publication status: PublishedFunder: Shield Therapeutics Ltd; Grant(s): 0000000Background and Aims: Altering dietary ferrous sulphate (FS) consumption exacerbates a murine model of colitis and alters the intestinal microbiome. We investigated the impact of oral ferric maltol (FM) and FS on mice with dextran sodium sulphate (DSS) induced colitis, and the microbiome of patients with iron deficiency. Methods: Mice had acute colitis induced, with 2% DSS for 5 days, followed by water. During this period, groups of mice were fed standard chow (200 ppm iron, SC, n = 8), or SC with 200ppm FS supplementation (n = 16, FSS), or SC with 200 ppm FM supplementation (n = 16, FMS). Clinical, pathological and microbiome assessments were compared at days 1 and 10. Fecal bacterial gDNA was extracted and the microbiome assessed by sequencing. Statistical inferences were made using MacQIIME. Principal Coordinates Analysis were used to visualize beta-diversity cluster analysis. Ten patients with IDA were treated with FS, and six with inactive inflammatory bowel disease received FM, supplements for four weeks: pre- and mid-treatment fecal samples were collected: the microbiome was assessed (see above). Results: In mice, after DSS treatment, there was a decrease in many genera in the SC and FSS groups: Lactobacillales increased in mice that received FMS. In humans, FS treatment led to an increase in five genera, but FM was not associated with any measurable change. The severity of DSS-induced colitis was greater with FSS than FMS. Conclusions: This study demonstrates differential and unique influences of ferric maltol and ferrous sulphate supplements on intestinal microbiota. These differences might contribute to the different side effects associated with these preparations